Advancing Precision Medicine Through Comprehensive Genomic Profiling (CGP) - Episode 4
Considerations regarding coverage decisions to support the large amount of information provided by molecular testing assays and the validity of results in terms of clinical decision-making.
Eugean Jiwanmall, MPH, MBA: I agree with a number of points that [Kenna] Shaw brought up….
Bruce Feinberg, DO: Doesn’t that sound like there’s a but coming? He’s going to agree to a lot of your points, but there’s a “but.”
Eugean Jiwanmall, MPH, MBA: I wanted to give her due with the doctorate she has. I agree with those points. I’m going to try to combine what Kenna said and a number of points that she has brought up. As our conversation expands, we’re going to bring up these concepts. I’m going to introduce some of the technical terms for the majority of the audience who are familiar with this. If not, we will definitely expand upon them. I’m going to say a number of things that should ring a bell.
The clinical validity portion when you’re doing a comprehensive genomic profiling becomes questionable at times. It’s highly unlikely that you’re going to have a genotype or phenotype correlation if you’re talking about hundreds of markers that are part of your test. We have to talk about that as our conversation goes on.… Coming back to the point about the variations that you may pick up, 1 term we’re probably going to depend on throughout this conversation is the variation of unknown significance. You’re going to be picking up the US part. The variation of unknown significance is definitely going to be picked up. This is the nature of the testing that’s out there. One thing, not just peers but in general—
Bruce Feinberg, DO: Hold on 1 second. I don’t want you to lose our audience. We have a mixed audience. You started getting into variations of unknown significance, and I’m afraid people are lost. We need clarity as to the mutations that are known and correlated and those that aren’t. Mark, we can go to you. It’s been known best in breast or around BRCA or other areas. Help this audience understand a little more.
Mark G. Kris, MD: BRCA is something different. BRCA is a prognostic test. It talks about a relative greater risk of developing a breast cancer. It’s a germline by and large.
Kenna R. Mills Shaw, PhD: Not anymore. We have to be careful with that.
Mark G. Kris, MD: When people talk about it, it’s inherited characteristic. There are therapeutic implications of it. When most people get a BRCA test, it’s to talk about cancer risk in them and their families.
Bruce Feinberg, DO: Just as an example, it wasn’t fair to me to give a breast example to a thoracic oncology guy.
Mark G. Kris, MD: We have to deal with this as well, and BRCA has significance as a somatic mutation as well. I guess we have a few different definitions: somatic vs germline.
Bruce Feinberg, DO: Germline.
Mark G. Kris, MD: Things in your DNA that you got from your parents and that you may pass on to your offspring vs mutations in the tumor. A lot of the talk about using the genetic determinants to choose therapies is based not on the germline but on the somatic mutations—changes in tumor. We all agree with that. Kenna, you seem to get bothered about the germline business. They’re different things, and it’s confusing for patients. We’re trying to keep this at a level that we all can understand. It’s really hard. One thing oncologists learn is to explain the difference between a germline and a somatic mutation. When you tell somebody you found a mutation in KRAS, they say, “Oh my god, did I pass that along to my daughter?” Then you need to explain that [they did not].
A couple of comments. No. 1, not all biomarkers are created equal. I grew up in this beta-mutation world, accused of being a “mutationist” along with my colleagues in Boston. There’s something about DNA—its analyzability; its reproducibility; the virtual lack of false positives, though there can be false negatives. That’s very different from a protein test.
Those of us who have followed the medical literature in breast cancer know how many hundreds of papers have been written rating degrees of protein expression in breast tumors and trying to use that grade as a way of determining successful therapies or prognoses. Once people noted amplification of certain genes were important, looking at the various fishnets. DNA is much more forgiving. It lasts a long time. It also has very few false positives. Most false negatives are due to sampling problems than not.
I want to make 1 important comment. We have agreement that there’s no test that tells you how to take care of somebody. It doesn’t exist. As a doctor, I’ve got to go back to first principles. You talk to the patient. You examine the patient. You get all the objective information you can from testing the patient and their tumor. You synthesize that into a diagnosis. Folks have an idea that you send the test to a company and get the answer. That’s absolutely not the case. People need to accept that it’s a piece of information. I don’t know. In some ways it’s easiest to focus on the prognostic piece because you use that diagnosis to choose therapy. Obviously, the predictive piece could be helpful. The diagnostic piece can be helpful. That’s a longer discussion that I don’t want to get into. The prognostic is the most important 1. If you have this abnormality in your tumor, then it gives you a certain likelihood of benefit from that therapy. In many ways, that’s the most useful.
Bruce Feinberg, DO: When you describe that, often it’s referred to as a driver mutation?
Mark G. Kris, MD: Yes.
Bruce Feinberg, DO: That DNA has mutated, and the result is going to cause it the change in the expression of protein that results in that cell behavior. If we interfere with that protein, then we can normalize that cell’s behavior or do something in a positive way.
Mark G. Kris, MD: Can I say a word here? It’s very helpful for people. Those cancer cells—I didn’t think this up—are addicted to that protein. They have to have that protein to survive, unlike your normal cells. If you deprive them of that, then they die.
Transcript edited for clarity.